Recently, a large superfamily of genes encoding deubiquitinating enzymes, called ubps, has been identified. Ubps are ubiquitin-specific thiol proteases. Deubiquitinating enzymes have multiple roles within the cell, including stabilization of some ubiquitin (Ub) conjugated substrates, degradation of other Ub-conjugated substrates and recycling of the cell's free monomeric Ub pool. Some deubiquitinating enzymes remove Ub from cellular target proteins and thereby prevent proteasome mediated degradation (UBP2). Other deubiquitinating enzymes remove Ub from Ub-peptide degradation products produced by the proteasomes and thereby accelerate proteasome mediated degradation (Doa-4). Little is known about the specific cellular functions of the ubp family members. The presence of multiple family members suggests considerable functional diversity. Disruption of ubp genes, in general, has not resulted in phenotypic variation, suggesting considerable functional redundancy among members of the superfamily.
Protein ubiquitination also serves regulatory functions that do not involve protein degradation (Hochstrasser al., Cell 84:813-815 (1995)). For example, Hicke and Riezman (Hicke and Riezman, Cell 84:277-287 (1996)) have recently demonstrated ligand inducible ubiquitination of the Ste2 receptor in yeast. Ubiquitination of the Ste2 receptor results in receptor endocytosis and receptor targeting to vacuoles, not proteosomes. Chen, et at. (Chen al., Cell 84:853-862 (1996)) have demonstrated that activation of the IKBa Kinase requires a rapid, inducible ubiquitination event. This ubiquitination event is a prerequisite for the specific phosphorylation of IKBa and does not result in subsequent proteolysis of the complex. Whether or not the ubiquitination of Ste2 or IKBa Kinase is reversible through the action of a specific deubiquitinating enzyme is not known.